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EASL Preview of Selected Abstracts (studies reported)
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The 41st Meeting of the European Association for the Study of Liver Diseases takes place in Vienna, Austria April 26-April 30. I will be attending and reporting in real-time important study results. Here is a preview of selected important studies with a brief explanation of the study aims. Of note there are several studies on new HCV drugs\HCV protease inhibitors, HCV polymerase inhibitors, a potential treatment for thrombocytopenia (low platelet counts), CPG 10101 (new toll-like receptor HCV therapy, an update on new HCV therapy Albuferon. There is an interesting study from Abbott examining boosting VX-950, the HCV protease inhibitor, with ritonavir, and a study of Pegasys maintenance therapy. Updates on important HBV drugs including those recently approved and in development.
Late Breakers Oral
INITIAL RESULTS OF A 14-DAY STUDY OF THE HEPATITIS C VIRUS INHIBITOR PROTEASE VX-950, IN COMBINATION WITH PEGINTERFERON-ALFA-2A (HW Reesink, abstract 737) VX-950 is a highly selective peptidomimetic inhibitor of the Hepatitis C virus (HCV) NS3„4A protease that is designed to block HCV replication. In a 14-day study reported previously, VX-950 monotherapy was well tolerated and had substantial antiviral effects, with every patient demonstrating at least a 2-log drop in viral load and a reduction in median HCV RNA of 4.4-log10 at the end of dosing in the best dose group. The current 14-day study was designed to explore the viral kinetics with VX-950 in combination with peginterferon- alfa-2a (Peg-IFN), and to assess safety. The VX04-950-103 clinical study randomized twenty treatment-naive patients with chronic genotype 1 hepatitis C infection to three dosing arms. Eight patients received VX-950 (750 mg as tablets q8h) plus Peg-IFN on Days 1 and 8 and eight patients received VX-950 alone. Four patients received Peg-IFN alone on Days 1 and 8.
A ONE YEAR RANDOMIZED, PLACEBO-CONTROLLED, DOUBLE-BLIND TRIAL OF ROSIGLITAZONE IN NON ALCOHOLIC STEATOHEPATITIS: RESULTS OF THE FLIRT PILOT TRIAL (VRatziu, abstract 738) Glitazones are promising drugs for nonalcoholic steatohepatitis (NASH) but only uncontrolled studies are available to date. Aim. To test the efficacy and safety of rosiglitazone vs. placebo in patients with NASH. Patients and Methods. Patients with biopsy-proven NASH with at least 20% steatosis were randomized to a one year treatment with rosiglitazone (RSG, 8 mg/day) or placebo (PLB). The primary end-point was an improvement in liver steatosis. Secondary end points were : normalization of transaminases, improvement in activity grade and fibrosis. Note from Jules Levin: it's been suggested that perhaps fatty liver ought to be treated first, before HCV therapy, perhaps resulting in improved SVR rates.
INTERIM RESULTS OF A MULTIPLE ASCENDING DOSE STUDY OF R1626, A NOVEL NUCLEOSIDE ANALOG TARGETING HCV POLYMERASE IN CHRONIC HCV PATIENTS (S Roberts, abstract 731) HCV polymerase is a promising target for the development of compounds for the treatment of HCV infection since it is an essential enzyme for HCV replication. R1626 is a prodrug of the nucleoside analog R1479, a potent inhibitor of HCV replication in vitro. A multiple ascending dose study was designed to evaluate the safety, tolerability, pharmacokinetics, and antiviral activity of R1479 in chronically HCV infected, treatment naive patients. Preliminary data are reported from this ongoing study. Patients (12 per dose cohort) were randomized 3:1 to oral treatment with R1626 or placebo for 14 days with 14 days of follow up. Two dose cohorts have been completed so far: 500 mg twice daily and 1500 mg twice daily. Assessments included safety, PK, and antiviral activity measured as serum HCV RNA levels.
THE SAFETY AND EFFICACY OF VIRAMIDINE PLUS PEGYLATED INTERFERON ALFA-2B VERSUS RIBAVIRIN PLUS PEGYLATED INTERFERON ALFA-2B IN THERAPY-NAIVE PATIENTS INFECTED WITH HCV: PHASE 3 RESULTS (Y Benhamou, abstract 751) Viramidine, a liver-targeting oral pro-drug of ribavirin, does not significantly accumulate in the red blood cell (RBC). Data from a phase 2 study revealed that dosing Viramidine 600 mg BID with pegylated-interferon resulted in comparable efficacy but significantly lower rates of anemia compared to ribavirin and pegylated-interferon. This fixed Viramidine dose (600 mg BID) was chosen for phase 3. Recently reported study results found FDA efficacy endpoints were not met delaying development of the drug and leading to post-hoc subset analysis and new study to find a utility for Viramidine.
EARLY VIRAL RESPONSE TO CPG 10101, IN COMBINATION WITH PEGYLATED INTERFERON AND/OR RIBAVIRIN, IN CHRONIC HCV GENOTYPE 1 INFECTED PATIENTS WITH PRIOR RELAPSE RESPONSE (JH McHutchison, abstract 730) CPG 10101 (CPG) is an investigational Toll-like receptor 9 (TLR9) agonist with antiviral activity. CPG activates plasmacytoid dendritic cells and B cells directly and NK/NKT cells indirectly, initiating and enhancing antiviral mechanisms mediated by both innate (antiviral cytokines including IFN-_) and adaptive immunity. This study investigates CPG's potential to exploit immune-mediated HCV infection control mechanisms when used with standard therapy in the relapsed subset of treatment-experienced patients. Seventy-four HCV genotype 1-infected adults who previously received ≥24 weeks PEG+RVN treatment resulting in undetectable HCV RNA levels and then relapsed with subsequent detection of HCV RNA within 6 months after cessation of treatment, were randomized and treated initially for 12 weeks in one of five arms: PEG+RVN, CPG+PEG+RVN, CPG+PEG, CPG+RVN, or CPG (CPG=0.2 mg/kg SC-weekly; PEG=1.5 _g/kg SC-weekly; RVN=800-1400 mg PO-daily).
PEGINTERFERON ALFA-2A (PEGASYS) PLUS RIBAVIRIN (COPEGUS) FOR 16 OR 24 WEEKS IN PATIENTS WITH HCV GENOTYPE 2 OR 3. FINAL RESULTS OF THE ACCELERATE TRIAL (ML Shiffman, abstract 734) The SVR achieved in HCV GT2 and 3 patients with 24wks of peginterferon alfa-2a (40KD)(PEGASYS) plus ribavirin (COPEGUS) is about 80%. This multinational study, the largest prospective study dedicated to this population, has examined if shortening this treatment to only 16wks could provide similar efficacy. 1469 treatment naive patients with GT2 or 3, elevated ALT, quantifiable serum HCVRNA (>600IU/mL) and compensated liver disease were randomised to receive 16 or 24wks of peginterferon alfa-2a (40KD) 180mg/wk plus ribavirin 800mg/d. Primary endpoint was SVR (HCVRNA <50IU/mL 24wks post-therapy). The study was a non-inferiority study powered to demonstrate equivalence within 6% between the two treatment groups based on the standard population (patients with no major protocol violations).
EARLY CLEARANCE OF HCV RNA WITH VALOPICITABINE (NM283) PLUS PEG-INTERFERON IN TREATMENT-NAIVE PATIENTS WITH HCV-1 INFECTION: FIRST RESULTS FROM A PHASE IIB TRIAL (D Dieterich, abstract 736) Many patients with HCV genotype 1 infection fail to achieve a sustained response to current therapy. Phase I-IIb clinical data indicate consistent dose-related anti-HCV activity for valopicitabine (NM283), alone and combined with pegylated interferon (NM283/pegIFN). An ongoing Phase IIb trial is evaluating NM283/pegIFN in treatment-naive patients with HCV-1. Due to GI side effects a lower dose than maximal dose used in studies conducted so far will be studied delaying development of NM283.
INTERIM (WEEK 12) PHASE 2B VIROLOGICAL EFFICACY AND SAFETY RESULTS OF ALBUMIN INTERFERON ALFA-2B COMBINED WITH RIBAVIRIN IN GENOTYPE 1 CHRONIC HEPATITIS C INFECTION (S Zeuzem, abstract 733) This ongoing Phase 2b, active controlled study evaluated the efficacy and safety of albumin interferon alfa-2b (alb-IFN), a novel recombinant protein consisting of IFNalfa-2b genetically fused to human albumin, in genotype 1, chronic HCV IFN-naive patients. 458 subjects were randomized into 4 SC treatment groups: Peg-IFNalfa-2a (Peg-IFN) (180 mcg Q1w) or one of 3 alb-IFN cohorts (900 mcg Q2w -every 2 weeks, 1200 mcg Q2w or 1200 mcg Q4w), all in combination with ribavirin (RBV) 1000-1200 mg/d based on body weight.
EFFECTS OF SATAVAPTAN (SR121463B), A SELECTIVE VASOPRESSIN V2 RECEPTOR ANTAGONIST, ON SERUM SODIUM CONCENTRATION AND ASCITES IN PATIENTS WITH CIRRHOSIS AND HYPONATRAEMIA (P Gines, abstract 732) Hyponatraemia in cirrhosis is associated with significant morbidity and mortality. Vasopressin receptor antagonists by increasing renal solute-free water excretion can potentially improve serum sodium concentration and reduce ascites. Aim: To investigate the effects of the addition of a vasopressin V2 receptor antagonist, satavaptan (SR121463B), to spironolactone on serum sodium and ascites in hyponatraemic patients with cirrhosis and ascites.
Late Breaker Posters
EFFICACY AND SAFETY OF ELTROMBOPAG, AN ORAL PLATELET GROWTH FACTOR, IN SUBJECTS WITH HCV ASSOCIATED THROMBOCYTOPENIA: PRELIMINARY RESULTS FROM A PHASE II DOSE-RANGING STUDY (JJG McHutchison, abstract 745) Eltrombopag olamine (SB-497115-GR) is an oral small molecule platelet growth factor that may be beneficial in patients with thrombocytopenia secondary to advanced liver disease. This ongoing study is designed to assess the safety and tolerability, efficacy and pharmacokinetics of repeat oral doses of eltrombopag in patients with HCV associated thrombocytopenia that precludes treatment with interferon/ribavirin according to recommended regulatory guidelines. Subjects with HCV infection, cirrhosis, compensated liver disease and platelet counts between 20-70,000/ul were enrolled.
SUSTAINED VIROLOGIC RESPONSE (SVR) TO INTERFERON-ALFA-2B+/- RIBAVIRIN THERAPY AT 6 MONTHS RELIABLY PREDICTS LONG-TERM CLEARANCE OF HCV AT 5-YEAR FOLLOW UP (JG MuHutchison, abstract 744) Absence of detectable serum HCV-RNA six months after treatment defines SVR. Data beyond six months is limited. Primary aim was to determine long-term SVR and clinical outcomes in patients treated with interferon-alfa-2b+/-ribavirin. Methods: 1071 patients treated with interferon-alfa-2b+/-ribavirin from six clinical trials were followed up to five years with annual measures of hematology, biochemistry, GI/liver examination and quantification of HCV RNA by PCR with sensitivity of 100 copies/ml (National Genetics Institute) and after 3/01 by Taqman (Schering-Plough: sensitivity of 29IU/ml).
SAFETY, TOLERABILITY AND ANTIVIRAL ACTIVITY OF PRADEFOVIR MESYLATE IN PATIENTS WITH CHRONIC HEPATITIS B VIRUS INFECTION: 48-WEEK ANALYSIS OF A PHASE 2 STUDY (KS Lee, abstract 741) Pradefovir (PDV) is a liver-targeted prodrug of PMEA with potentially improved efficacy and less nephrotoxicity than adefovir dipivoxil (ADV). Aims: To evaluate the safety and efficacy of PDV in chronic HBV infection. Methods: Randomized, open-label, parallel-group, multicenter study comparing ADV 10 mg/d and PDV 5, 10, 20, and 30 mg/d for 48 weeks.
PRECLINICAL CHARACTERISTICS OF ITMN-B, AN ORALLY ACTIVE INHIBITOR OF THE HCV NS3/4A PROTEASE NOMINATED FOR PRECLINICAL DEVELOPMENT (SD Seiwert, abstract 750) Novel therapeutic approaches for the treatment of chronic HCV are needed as current therapies provide sustained virologic response rates of ~50%. Inhibition of the HCV serine protease, NS3/4A, represents a promising new therapeutic strategy. Here we describe the preclinical characterization of ITMN-B, an active site inhibitor that emerged from our discovery program and was nominated as a preclinical candidate.
THE MAJORITY OF PATIENTS WITH HBEAG-NEGATIVE CHRONIC HEPATITIS B TREATED WITH PEGINTERFERON ALFA-2A (40KD) [PEGASYS] SUSTAIN RESPONSES 2 YEARS POST-TREATMENT (PMarcellin, abstract 743) In HBeAg-negative chronic hepatitis B (CHB) patients, PEGASYS provides a significantly better sustained response 6 months after treatment completion than lamivudine [Marcellin et al, 2004]. The aim was to evaluate the durability of response 2 years after conclusion of treatment in patients given PEGASYS monotherapy.
Oral Presentations
FINAL RESULTS OF A MULTI-CENTER PHASE 1B, RANDOMIZED, PLACEBO-CONTROLLED, DOSE-ESCALATION TRIAL OF CPG 10101 IN PATIENTS WITH CHRONIC HEPATITIS C VIRUS (JG McHutchison, abstract 111) CPG 10101 (ActilonTM) is an investigational, synthetic Toll-like Receptor 9 (TLR9) agonist being developed as an antiviral and Th1 immune enhancer for treatment of chronic hepatitis C virus (HCV) infection. CPG 10101 binds to TLR9 receptors on human B cells and plasmacytoid dendritic (pDC) cells, initiating and enhancing both innate and adaptive immune responses that support the proposed antiviral mechanisms of CPG 10101, including cytokine release and activation of antigen presenting and B and T effector cells. A multi-center Phase 1b trial randomized 60 HCV+ patients (predominantly genotype 1 who failed previous therapy) to CPG 10101 or placebo (6:2) in 5 sequential dose cohorts (0.25, 1, 4, 10, or 20 mg SC) given twice weekly for 4 weeks or 2 sequential weight-based dose cohorts (0.5 or 0.75 mg/kg SC) given once weekly for 4 weeks. Tolerability, pharmacokinetics, pharmacodynamics (2'5'-OAS, CRP, IFN-_, IFN-_, IL-18, IP-10, MCP-1, MIP-3B), immunophenotyping, and HCV RNA level were evaluated during and for 4 weeks after treatment.
A PHASE 2 DOSE-ESCALATION STUDY OF ALBUFERON COMBINED WITH RIBAVIRIN IN NON-RESPONDERS TO PRIOR INTERFERON BASED THERAPY FOR CHRONIC HEPATITIS C INFECTION (V Rustgi, abstract 113) Albuferon (alb-IFN) is a novel recombinant protein consisting of IFNa genetically fused to human albumin. This ongoing Phase 2, dose-ranging study evaluates the safety and efficacy of Albuferon in chronic HCV patients who were non-responders (failed to achieve EVR12 or clear HCV RNA) to previous IFNa based regimens. Subjects were randomized into 3 alb-IFN SC treatment cohorts (900 mcg Q2w, 1200 mcg Q2w or 1200 mcg Q4w, every 4 weeks) in combination with ribavirin (RBV) 1000-1200 mg/d. After evaluating safety data, 2 higher dose treatment cohort of alb-IFN 1500 mcg Q2w (every 2 weeks) and 1800 mcg Q2w were enrolled. The treatment duration is 48w with 24w follow-up and the primary efficacy end-point is SVR. Currently 8w data for the highest dose and >24w data for other cohorts is available.
MULTICENTER RANDOMIZED TRIAL OF HCV TREATMENT WITH PEGINTERFERON-ALFA 2A AND RIBAVIRIN IN LIVER TRANSPLANT PATIENTS WITH ESTABLISHED RECURRENT HEPATITIS C: INTERIM ANALYSIS (C Duvoux, Abstract 1) End-stage liver disease (ESLD) secondary to hepatitis C virus (HCV) infection is one of the most common indication for liver transplantation (OLT). Infection of the graft is universal, causing histologic injury and graft loss in 6% -28% by the fifth postoperative year. Objective: to investigate wether a one year maintenance therapy of Ribavirin (RBV) could increase viral HCV eradication after a one year combination therapy with peginterferon alfa 2a (Pegasys ) plus RBV (Copegus ). Interim results of the one year combination therapy are presented.
SAFETY AND EFFICACY OF ADEFOVIR DIPIVOXIL IN PATIENTS WITH LAMIVUDINE-RESISTANT CHRONIC HEPATITIS B UNDERGOING LIVER TRANSPLANTATION (E Schiff, abstract 2) Lamivudine and HBIg prevent reinfection of the graft following liver transplantation for chronic hepatitis B (CHB), however, lamivudine resistance can develop and HBIg is costly. The efficacy and safety of adefovir dipivoxil (ADV) and lamivudine in preventing reinfection in patients with lamivudine-resistant CHB were investigated.
A MULTICENTER ITALIAN STUDY OF RESCUE ADEFOVIR DIPIVOXIL THERAPY IN LAMIVUDINE RESISTANT PATIENTS: A 2-YEAR ANALYSIS OF 650 PATIENTS (PLampertico, abstract 116) Aim of the study was to evaluate the rates of virological response, adefovir resistance (ADV-R), side effects and liver related-complications in a large cohort of Italian patients treated with Adefovir dipivoxil (ADV) for LAM-R. 650 LAM-R patients who started ADV treatment between 2002 and 2004 in 27 Italian centers were enrolled in a prospective cohort study and followed for 18 months, on average. Mean age was 54 years, 81% were men, 85% HBeAg-negative, 49% cirrhotics; 51% of the patients switched from LAM to ADV (ADV mono group) while 49% added ADV to LAM (combo group).
PHARMACOKINETIC BOOSTING OF VX-950, AN INHIBITOR OF HCV PROTEASE, BY CO-DOSING WITH RITONAVIR (D Kempf, abstract 4) HCV protease inhibitors (PIs) are a promising new class of small-molecule, peptidomimetic HCV antivirals. In initial clinical studies, antiviral activity has been associated with HCV PI plasma trough concentrations. However, modest pharmacokinetics and the need for frequent dosing may limit their efficacy. Co-dosing with ritonavir (RTV), a potent inhibitor of CYP3A, has proven useful for pharmacokinetic enhancement of peptidomimetic HIV PIs, which are metabolized by this enzyme. We investigated the in vitro and in vivo interaction of the HCV PI VX-950 with RTV.
NATURAL HISTORY AND OUTCOME OF ACUTE HEPATITIS C IN PATIENTS WITH END STAGE RENAL DISEASE (S Kamal, abstract 7) Hepatitis C virus (HCV) infection represents a problem for patients with end-stage renal disease (ESRD) and renal transplants. HCV infection is associated with significant worsening of survival on dialysis therapy, as well as after kidney transplantation.. The source of HCV infection in these patients can be nosocomial. This prospective randomized trial assessed the efficacy safety and optimal therapeutic dose of pegylated interferon alfa-2b for treatment of acute hepatitis C acquired during hemodialysis. Patients with ESRD were screened for HCV before starting hemodialysis then monthly after hemodialysis (ALT, serum HCV RNA and anti-HCV antibodies). Patients
24 WEEK TREATMENT REGIMEN WITH PEGINTERFERON ALFA-2A (40KD) (PEGASYS) PLUS RIBAVIRIN (COPEGUS ) IN HCV GENOTYPE 1 OR 4 'SUPER-RESPONDERS' (P Ferenci, abstract 8) Retrospective analysis suggests shorter schedules may be suitable for genotypes 1 or 4 patients with undetectable HCV RNA at week 4. Conversely, longer treatment may be needed in patients with a slow response to therapy. Consequently, a prospective randomised multi-centre trial was initiated to examine customising therapy according to virological responses at week 4 and 12 in genotype 1 or 4 patients. Herein we report data from patients with undetectable HCV RNA at week 4 of therapy. Interferon-naive adults with chronic hepatitis C and quantifiable HCV RNA genotype 1 were enrolled. All received peginterferon alfa-2a (40KD) (PEGASYS ) 180 mg/week plus ribavirin (COPEGUS ) 1000/1200 mg/day. At week 4, 'super-responders' (undetectable HCV RNA, <50 IU/mL) were assigned to group D and received a further 20 weeks' therapy. To date, 424 patients have been enrolled with 358 treated for 12 weeks.
PHASE II, MULTI-CENTRE, DOSE-ESCALATING STUDY OF LB80380 (ANA380) IN HEPATITIS B PATIENTS WITH LAMIVUDINE-RESISTANT YMDD MUTANT HBV
(CL Lai, abatract 6) LB80380 (also termed ANA380) is a novel antiviral agent that is converted after administration to LB80317, a novel guanosine phosphonate nucleotide analogue that exhibits potent activity against HBV, including in vitro activity against HBV variants resistant to lamivudine. This study investigates the safety and antiviral activity of escalating doses of LB80380 in HBeAg+ patients with lamivudine-resistant HBV. 65 patients were enrolled into 5 cohorts.
EFFICACY OF STANDARD-DOSE AND FIXED-DOSE INDUCTION PEGINTERFERON ALFA-2A (40KD) (PEGASYS) PLUS RIBAVIRIN (COPEGUS) AMONG PEGYLATED INTERFERON ALFA-2B (12KD)/RIBAVIRIN NON-RESPONDERS: INTERIM ANALYSIS OF THE REPEAT STUDY (P Marcellin, abstract 11) REPEAT will assess the efficacy/safety of Peg-IFNa-2a (40KD) plus ribavirin in previous non-responders to Peg-IFNa-2b (12KD)/ribavirin. We report results of a protocol-planned efficacy analysis after 12 weeks. Non-responders to ≥12 weeks of Peg-IFNa-2b (12KD)/ribavirin at approved doses who remained HCV-RNA-positive throughout treatment were eligible. 950 patients were randomised to one of four groups: Peg-IFNa-2a (40KD) 360mg/week for 12 weeks then 180mg/week for 60 or 36 weeks (Arms A and B); Peg-IFNa-2a (40KD) 180mg/week for 72 or 48 weeks (Arms C and D). All patients received 1000/1200mg/day ribavirin.
WILD-TYPE HCV NS3 PROTEASE RE-EMERGES DURING FOLLOW-UP AFTER 14 DAYS OF DOSING WITH VX-950 IN PATIENTS WITH GENOTYPE 1 HCV (T Kieffer, abstract 12) VX-950 is an oral HCV protease inhibitor that profoundly reduced plasma HCV RNA in genotype 1 patients during 14 days of dosing. The subset of patients defined by a continuous decline in HCV RNA levels (median 4.8 log10) also had the highest mean VX-950 trough concentrations. Two other subsets of patients experienced a rapid decrease in HCV RNA followed by a plateau or breakthrough response, which correlated with lower VX-950 plasma concentrations. Using a highly sensitive sequencing assay that detects minor populations (<5%), plateau and breakthrough response correlated with selection of virus containing 1 or 2 mutations in the NS3 protease region. Mutations at positions V36, T54, or R155 confer low-level resistance in vitro (small increase in enzymatic VX-950 IC50) and mutation at position A156 confers high-level resistance. We now report variant prevalence post-dosing, in the absence of drug selective pressure.
RISK OF HEPATOCELLULAR CARCINOMA ASSOCIATED WITH GENOTYPES AND MUTANTS OF HEPATITIS B VIRUS: A COMMUNITY-BASED PROSPECTIVE COHORT STUDY (HI Yang, abstract 27) The roles of genotypes and mutants of hepatitis B virus (HBV) in hepatocarcinogenesis remain to be elucidated. The specific aim of this long-term follow-up study was to assess the risk of hepatocellular carcinoma (HCC) associated with HBV genotypes, precore stop codon mutant (G1896A) and basal core promoter mutant (A1762T/G1764A).
VALOPICITABINE (NM283), ALONE OR WITH PEG-INTERFERON, COMPARED TO PEG INTERFERON/RIBAVIRIN (PEGIFN/RBV) RETREATMENT IN HEPATITIS C PATIENTS WITH PRIOR NON-RESPONSE TO PEGIFN/RBV: WEEK 24 RESULTS
(N Afdahl, abstract 39) HCV genotype 1 non-responders (NR) to pegIFN/RBV comprise over 50% of currently treated patients and have no proven treatment options. NM283 has shown anti-HCV activity alone and in combination with pegIFN in Phase I-IIa trials, without viral breakthrough for study periods up to 6 months. NM283 was set to enter phase III but development has been delayed as new study has been designed to evaluate lower dosing due to GI side effects at higher doses used in studies.
DIFFERENCES IN TREATMENT OUTCOME TO ANTIVIRAL THERAPY BASED ON GENOTYPE AND VIRAL LOAD IN HEPATITIS C GENOTYPES 2 AND 3 IN THE WIN-R TRIAL (RS Brown, abstract 41) WIN-R, a multicenter, randomized, open-label, investigator-initiated trial in 225 US sites between 12/00 and 6/05 randomized treatment-naive adults HCV patients with compensated liver disease to receive PEG-IFN alfa-2b 1.5 _g/kg/week plus fixed dose ribavirin (800 mg/day) or weight-based dosing ribavirin (800 mg/day for weight <65 kg, 1,000 mg/day for 65-85 kg, 1,200 mg/day for >85-105 kg, 1,400 mg/day for >105-125 kg). G2 and G3 patients were also randomized to receive 24 or 48 weeks of therapy. HCV RNA was assessed at weeks 0, 24, 48 and 72. The primary endpoint was SVR (absence of detectable HCV RNA at week 72) in patients ≥65 kg. SVR rates were similar in the WBD and FD groups (68 vs. 65%). Objective: To determine the predictors of response to PEG-IFN alfa-2b plus ribavirin in patients with HCV G2 and G3.
CONTINUED VIROLOGIC AND BIOCHEMICAL IMPROVEMENT THROUGH 96 WEEKS OF ENTECAVIR TREATMENT IN HBEAG(-) CHRONIC HEPATITIS B PATIENTS (STUDY ETV-027) (D Shouval, abstract 45) Entecavir (ETV) demonstrated superior virologic, biochemical and histologic benefit compared to lamivudine (LVD) at Week 48 in HBeAg(-) chronic hepatitis B (CHB) patients. HBV DNA suppression to <300 copies/mL occurred in 90% of ETV patients and 72% of LVD patients. Efficacy and safety through 96-weeks of treatment is reported here.
ENTECAVIR RESULTS IN CONTINUED VIROLOGIC AND BIOCHEMICAL IMPROVEMENT AND HBEAG SEROCONVERSION THROUGH 96 WEEKS OF TREATMENT IN LAMIVUDINE-REFRACTORY, HBEAG(+) CHRONIC HEPATITIS B PATIENTS (ETV-026) (CYurdaydin, abstract 80) In lamivudine (LVD)-refractory, HBeAg(+) chronic hepatitis B (CHB) patients, switching to entecavir (ETV) was superior to continued LVD at Week 48 for achieving histologic improvement, undetectable HBV DNA and ALT normalization. Long-term data for efficacy and safety through 96 weeks of treatment are reported here.
DURABILITY OF RESPONSE AND OCCURRENCE OF LATE RESPONSE TO PEGINTERFERON ALFA-2A (40KD) [PEGASYS] ONE YEAR POST-TREATMENT IN PATIENTS WITH HBEAG-POSITIVE CHRONIC HEPATITIS B (GKK Lau, abstract 50) In patients with HBeAg-positive chronic hepatitis B (CHB), peginterferon alfa-2a (40KD) [PEGASYS] provides significantly higher rates of HBeAg seroconversion and HBV DNA response (HBV DNA <100,000 copies/ml) 6 months post-treatment versus lamivudine [Lau, NEJM 2005]. We evaluated response 1 year after the end-of-treatment in patients receiving peginterferon alfa-2a alone.
HIGH BARRIER TO RESISTANCE RESULTS IN NO EMERGENCE OF ENTECAVIR RESISTANCE IN NUCLEOSIDE-NAIVE SUBJECTS DURING THE FIRST TWO YEARS OF THERAPY (R Colonno, poster abstract 490) Background: Entecavir (ETV) is a highly effective inhibitor of hepatitis B virus (HBV) replication. Lamivudine-resistance (LVDr) substitutions (M204V/I ± L180M) reduce ETV susceptibility 8-fold, while virologic rebound due to ETV resistance (ETVr) requires pre-existing LVDr substitutions plus additional changes at RT residues T184, S202 and/or M250 that can be selected by LVD. ETV-treated patients experiencing virologic rebounds (>1 log increase from nadir by PCR) or failing to reduce their HBV DNA levels to <300 copies/ml by Week 96 in studies AI463-022, AI463-027 and AI463-901, were analyzed for emerging ETVr by genotypic analysis and phenotypic susceptibility assays.
TENOFOVIR (TNV) HAS STRONGER ANTIVIRAL EFFECT THAN ADEFOVIR DIPIVOXIL (ADV) AGAINST LAMIVUDINE (LAM) RESISTANT HEPATITIS B VIRUS (HBV) (HW Hann, poster abstract 495) Chronic hepatitis B (CHB) patients with LAM resistance were treated with TNV or ADV. In some, LAM was continued or added later. In this retrospective study we compared the suppressive activities of TNV and ADV against LAM resistant HBV. 109 patients (86 males), all Asian-American except 1 white male, received TNV or ADV. Reduction of HBV DNA and ALT normalization were measured at 6 and 12 mos on therapy. HBeAg loss was assessed in 24 mos.
OPTIMAL VIROLOGIC AND CLINICAL EFFICACY AT ONE YEAR IS ASSOCIATED WITH MAXIMAL EARLY HBV SUPPRESSION IN NUCLEOSIDE-TREATED HEPATITIS B PATIENTS (S Zeuzem, abstract 51) Maximal early reduction of serum viral load has been associated with improved treatment outcomes and less resistance in hepatitis B patients. The GLOBE trial is a phase III randomized comparison of telbivudine (LdT) vs lamivudine; this large database allows a more definitive assessment of links between early virologic response and subsequent virologic and clinical efficacy. The GLOBE trial enrolled 1,367 hepatitis B patients, stratified by HBeAg status. For the present analysis, patients were categorized according to HBV DNA levels at Week 24 (W24) as shown in the Table. Efficacy outcomes at 1 year were assessed in relation to these W24 viral load categories.
A RANDOMIZED TRIAL OF TELBIVUDINE (LDT) VS. ADEFOVIR FOR HBEAG-POSITIVE CHRONIC HEPATITIS B: RESULTS OF THE PRIMARY WEEK 24 ANALYSIS (HLY Chan, abstract 52) For optimizing patient management with the current antiviral armamentarium for hepatitis B, additional comparative studies are needed. This ongoing 1-year international trial is comparing the antiviral efficacy and safety of telbivudine vs adefovir. The enrolled ITT population is 133 adults with HBeAg-positive chronic hepatitis B.
TELBIVUDINE DISPLAYS CONSISTENT ANTIVIRAL EFFICACY ACROSS PATIENT SUBGROUPS FOR THE TREATMENT OF CHRONIC HEPATITIS B: RESULTS FROM THE GLOBE STUDY (S Thongsawat, abstract 110) Telbivudine (LdT) demonstrated significantly greater antiviral efficacy compared with lamivudine (Lam) in a large international phase III trial (GLOBE study). In this analysis, the influence of baseline demographic parameters on 1-year efficacy outcomes is assessed. Treatment groups were well-matched at baseline. Key demographic and viral subgroups (HBV genotype, gender, age and ethnicity) were examined for effect on virologic response, evaluated as log10 HBV DNA reduction and PCR negativity (HBV DNA <300 copies/mL), in both HBeAg-positive and HBeAg-negative patients.
PHASE III COMPARISON OF TELBIVUDINE VS LAMIVUDINE IN HBEAG-POSITIVE PATIENTS WITH CHRONIC HEPATITIS B: EFFICACY, SAFETY, AND PREDICTORS OF RESPONSE AT 1 YEAR (R Gish, poster abstract 493) The GLOBE trial is a 2-year phase III randomized comparison of telbivudine vs lamivudine in 921 HBeAg-positive and 446 HBeAg-negative adults with chronic hepatitis B from 20 countries. We report the primary efficacy and safety results at 52 and 76 weeks and determine the predictors of efficacy for HBeAg-positive patients in this international trial.
HBV RESISTANCE DETERMINATION FROM THE TELBIVUDINE GLOBE REGISTRATION TRIAL (DN Standring, poster abstract 514) The safety and efficacy of telbivudine are being evaluated in a large, international randomized trial (the GLOBE trial) involving 1367 patients with chronic hepatitis B. Here we report detailed analysis of HBV genotypes and treatment-emergent breakthrough and resistance after 1 year. HBV genomes were amplified from sera of study patients by RT PCR. The 344 amino acid polymerase RT domain was sequenced to determine baseline HBV genotypes. Patients experiencing breakthrough were re-sequenced at week 48 or post-breakthrough to identify resistance mutations. In vitro studies in stably transfected cell-lines evaluated potential cross-resistance with lamivudine and adefovir.
ONE-YEAR TREATMENT WITH CLEVUDINE DEMONSTRATED SIGNIFICANT VIRAL SUPPRESSION AND BIOCHEMICAL IMPROVEMENT (YH Chung, abstract 53) In the pivotal phase III clinical trials, clevudine showed potent antiviral activity along with a marked post-treatment antiviral effect. Objectives: To evaluate the effect of 1-year treatment with clevudine in treatment-naive or clevudine-experienced patients. Safety, antiviral activity, biochemical improvement and serologic response were monitored in patients receiving clevudine 30 mg for 24 weeks followed by clevudine 10 mg for an additional 24 weeks as a maintenance therapy with a 12-week follow-up period. Preliminary results from the first 31 naive patients (25 HBeAg(+), 6 HBeAg(-)) who have completed the treatment phases are presented here.
THE HCV NS3 PROTEASE INHIBITOR SCH 503034 IN COMBINATION WITH PEG-IFN-ALPHA-2B IN THE TREATMENT OF HCV-1 PEG-IFN-ALPHA-2B NON-RESPONDERS: ANTIVIRAL ACTIVITY AND HCV VARIANT ANALYSIS (S Zeuzem, abstract 78) The Hepatitis C virus (HCV) NS3 protease is critical for viral replication and may inhibit host responses to endogenous and exogenous IFN. SCH 503034 is a novel, orally available HCV NS3 protease inhibitor. In this study the safety, antiviral activity, and emergence of resistant strains of SCH 503034 plus PEG-IFN-_2b was evaluated in HCV-1 PEG-IFN-_2b non-responders. This was a multi-center, open-label study, in which adults with HCV-1 who previously failed PEG-IFN- _ 2b ± Ribavirin therapy (<2 log reduction in HCV RNA after 12 wks) received in random sequence, A) SCH 503034 oral capsules (200 mg or 400 mg) as a monotherapy for 7d, B) PEG-IFN- _ 2b (1.5 mcg/kg/QW) as monotherapy for 14d, and C) PEG-IFN- _ 2b (1.5 mcg/kg/QW) + SCH 503034 (200 mg or 400 mg) for 14d, in a 3-way crossover design with a 2-3-wk washout between treatments. HCV RNA viral load was determined by real-time PCR (Taq-Manž/LOQ= 29 IU/ml) and selection of variants under antiviral therapy assessed by direct sequencing. Safety was assessed by clinical laboratory values, ECG, vital signs and adverse events.
FURTHER REDUCTION OF RIBAVIRIN DOSE IN HCV GENOTYPE 2/3 PATIENTS RECEIVING PEGINTERFERON ALFA-2A (40KD) (PEGASYS) PLUS RIBAVIRIN (COPEGUS): INTERIM RESULTS OF A RANDOMISED CONTROLLED TRIAL (P Ferenci, abstract 82) Similar SVR rates have been observed with 24 weeks' peginterferon alfa-2a (40KD) (PEGASYS ) plus ribavirin (COPEGUS ) 1000/1200 and 800mg/day in genotype 2/3 patients; current guidelines, therefore, recommend ribavirin 800mg/day. However, because anaemia can still occur with a ribavirin dose of 800mg/day, we investigated whether this could be further reduced to 400mg/day.
SAFETY AND PHARMACOKINETICS OF THE NON-NUCLEOSIDE POLYMERASE INHIBITOR, HCV-796: RESULTS OF A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, ASCENDING SINGLE-DOSE STUDY IN HEALTHY SUBJECTS (P Chandra, poster abstract 561) HCV-796 is an inhibitor of hepatitis C virus (HCV) RNA-dependent RNA polymerase that has demonstrated potent antiviral activity in vitro. The purpose of this study was to assess the safety, tolerability, and pharmacokinetics of ascending, single oral doses of HCV-796 in healthy subjects. A phase 1, randomized, double-blind, placebo-controlled, ascending, single-dose study of orally administered HCV-796 was conducted. Healthy subjects aged 18 to 45 years received 25, 50, 100, 250, 500, 1000, or 2000 mg oral doses of HCV-796 or placebo (6 active, 2 placebo per dose group). Subjects in the 100 mg dose cohort received HCV-796 in a fasting and fed state.
LONG-TERM LOW DOSE TREATMENT WITH PEGYLATED INTERFERON ALFA "B LEADS TO A SIGNIFICANT REDUCTION IN FIBROSIS IN CHRONIC HEPATITIS C NONRESPONDER PATIENTS (S Kaiser, poster abstract 584) Treatment with current standard antiviral therapy leaves about 50% of patients without viral clearance with the risk of progression of their liver disease. Recent studies have suggested an antifibrotic effect of low dose interferon treatment.The efficacy of low dose pegylated interferon alfa 2b with 0.5 ug/kg weekly given for 36 months as monotherapy was evaluated based on histological examination and liver function in patients with chronic HCV, nonresponse to antiviral combination therapy and significant fibrosis / cirrhosis and compared to an observational control group (n=60). Histology was evaluated at baseline, at 18 months of treatment and 6 months after end of treatment.
INSULIN RESISTANCE IN CO-INFECTED HCV/HIV PATIENTS: A NEGATIVE FACTOR INFLUENCING SUSTAINED RESPONSE TO PEGINTERFERON PLUS RIBAVIRIN (M Romero-Gomez, poster abstract 603) Background: Insulin resistance (IR) diminishes the likelihood of achieving a sustained virological response (SVR) to HCV antiviral therapy in HCV+/HIV- patients. There is no information about the association of IR with the efficacy of such treatment in HCV+/HIV+ patients. Objectives: To evaluate the independent predictors of SVR in a cohort or 198 patients (113 HCV+/HIV+ and 85 HCV+/HIV-).
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